Brain sigma receptors are the subject of intense investigation in light of the fact that sigma receptors bind many psychotropic drugs (Sonders et al., Trends Neurosci., 1: 37-40 (1988)). Moreover, certain sigma receptor ligands have antipsychotic activity which suggests that sigma receptor active compounds may be used for the treatment of schizophrenia (Largent et al., Eur. J. Pharmacol., 11: 345-347 (1988)).
Certain neuroleptic (i.e., antipsychotic) agents bind with very high affinity at sigma sites. Su, T., J. Pharmacol. Exp. Ther., 223: 284 (1982); Tam, S. W., Proc. Nat. Acad. Sci (USA), 80: 6703 (1983). One agent with very high affinity for sigma sites (Ki ca 1 nM; i.e., approximately 100-fold higher affinity than N-allyl normetazocine (NANM) is the neuroleptic agent haloperidol. Tam, S. W., et al., Proc. Nat. Acad. Sci (USA), 81: 5618 (1984). Sigma-opiates, such as NANM, bind with low affinity at typical opiate receptors but bind with significant affinity at PCP receptors.
Current neuroleptic agents are thought to produce their effects via a dopaminergic (DA) mechanism; they display very high affinities for DA binding sites. However, not all of the potent neuroleptic agents bind at [.sup.3 H]NANM-labelled sigma sites, nor do the sigma-opiates bind at DA sites. This has led to the suggestion that the sites labelled by [.sup.3 H]NANM be termed sigma-sites and not sigma-opiate sites (i.e., it may simply be coincidental that the sigma opiates possess an opiate-like chemical structure). In addition, there has been speculation that agents with high affinity for sigma sites may either (a) produce psychotic effects (if they behave as agonists), or (b) produce antipsychotic effects (if they behave as antagonists). It has further been speculated that certain neuroleptic agents, such as haloperidol, produce their antipsychotic effects by both a sigma and DA mechanism. Tam, S. W. and Cook, L., Proc. Nat. Acad. Sci. (USA), 81: 5618 (1984). In fact, [.sup.3 H]haloperidol, in combination with spiperone (an agent with high affinity for DA sites and essentially no affinity for sigma sites) is now commonly used to label sigma sites in radioligand binding studies.
A number of researchers have studied the structure-activity relationship of sigma ligands. For example, Manallack, D. T., et al., Eur. J. Pharmacol., 144: 231-235 (1987), disclose a receptor model for the phencyclidine and sigma binding sites. Manallack et al. disclose that in a recent SAR study (Largent et al., in press), sigma site affinity was shown to be enhanced by large N-alkyl substituents, e.g., benzyl or phenylethyl.
Largent, B. L., et al., Mol. Pharmacol., 32: 772-784 (1987), disclose a study of the structural determinants of sigma receptor affinity. In particular, Largent et al. teach that several piperidine and piperazine derivatives have sigma receptor activity. Largent et al. also disclose that affinity for the sigma receptor is markedly influenced by the N-alkyl substituents, with more lipophilic substituents affording greater affinity for the sigma receptor binding sites.
Sharkey, J., et al., Eur. J. Pharmacol., 149: 171-174 (1988), studied the sigma receptor binding activity of cocaine-related compounds.
The literature contains a number of suggestions that the sigma receptor is not a single, homogeneous binding site. Bowen, W. D. et al., Eur. J. Pharm., 163: 309-318 (1989), disclose that the effect of U.V. radiation on sigma receptor binding depended on the radioligand used to assay for it. It was also demonstrated that the binding characteristics of several sigma ligands were different in membranes from certain cell lines than in guinea pig brain membranes. (Hellewell, S. B. and Bowen, W. D., Brain Res., 527: 224-253 (1990); Wu, X. Z. et al., J. Pharmacol. Exp. Ther., 257: 351-359 (1991)). At least two groups have reported significantly different pharmacology for "sigma receptors" when using different radioligands to label these sites. (Itzhak, Y., et al., J. Pharmacol. Exp. Ther., 257: 141-148 (1991); Karbon, E. W., et al., Eur. J. Pharm., 93: 21-27 (1991)). In addition, [.sup.3 H]DTG binding was found to have two components in guinea pig membranes (Rothman, R. B. et al., Mol. Pharm., 39: 222-232 (1991)). An overlap of sigma sites with some of the multiple sites labeled by [.sup.3 H]dextromethorphan has also been described (Musacchio, J. M., et al., Life Sci., 45: 1721-1732 (1989)).
Hellewell and Bowen, Brain Res., 527: 224-253 (1990), were the first to define the characteristics of the two putative sigma receptor subtypes, named sigma-1 and sigma-2. The primary pharmacological distinction between these two sites is the affinity of the (+) isomers of the benzomorphan opiates for the binding sites. These compounds, such as (+)SKF 10,047 (NANM) and (+)pentazocine show nearly two orders of magnitude higher affinity for the sigma-1 site compared to the sigma-2 site. The (-) isomers of the benzomethorphans show little selectivity between these two sites. Other distinctions noted between the two sites are a preponderance of the sigma-2 sites in cell lines such as NCB-20, PC12 and NG108-15 cells (Hellewell, S. B. and Bowen, W. D., Brain Res., 527: 224-253 (1990); Wu, X. -Z., et al., J. Pharmacol. Exp. Ther., 257: 351-359 (1991); George, A. and Friedl, A., J. Pharmacol. Exp. Ther., 259: 479-483 (1991); Quirion, R., et al., Trends in Pharmacological Sciences, 13: 85-86 (1992)).
There has been considerable research on amphetamine and amphetamine derivatives which were not examined for sigma receptor activity (nor are they believed to possess much of such activity). See, e.g., Aldous, F. A. B., J. Med. Chem., 17: 1100-1111 (1974); Fuller, R. W. et al., J. Med. Chem., 14: 322-325 (1971); Foye, W. O. et al., J. Pharm. Sci., 68: 591-595 (1979); Boissier, J. R. et al., Chem. Abstr., 66: 46195h (1967); Boissier, J. R. et al., Chem. Abstr., 67: 21527a (1967); Osbond, J. M. et al., Chem. Abstr., 69: 51816c (1968); Gosztonyi, T. et al., J. Label. Comp. Radiopharm., 8: 293-303 (1977); Coutts, R. T. et al, Can. J. Microbiol., 26: 844-848 (1980); Fuller, R. W. et al., J. Pharm. Pharmacol. 25: 828-829 (1973); Fuller, R. W. et al., Neuropharmacology, 14: 739-746 (1975); Conde, S. et al., J. Med. Chem., 21: 978-981 (1978); Lukovits, I., Int. J. Quantum. Chem., 20: 429-438 (1981); Law, B., J. Chromatog., 407: 1-18 (1987); Johansson, A. M. et al., J. Med. Chem., 30: 602-611 (1987); Hacksell, U. et al., J. Med. Chem., 22: 1469-1475 (1979); McDermed, J. D. et al., J. Med. Chem., 18: 362-367 (1975); Glennon, R. A. et al, Pharmacol. Biochem. Behav., 21: 895-901 (1984); Beaulieu, M. et al., Eur. J. Pharmacol., 105: 15-21 (1984); Naiman, N. et al., J. Med. Chem., 32: 253-256 (1989); Beecroft, R. A. et al., Tetrahedron, 41: 3853-3865 (1985); Fuller, R. W., et al., J. Pharmacol. Exp. Therapeut., 218: 636-641 (1981); Fuller, R. W. et al., Res. Commun. Chem. Pathol. Pharmacol., 29: 201-204 (1980); Boissier, J. et al., Chem. Abstr., 61: 10691 c; Roessler, Chem Abstr., 61: 13328g; Ruschig, H., et al., Chem. Abstr., 53: 3253e; Shvedov, V. I., et al., Chem. Abstr., 73: 11806q (1970); Popov, D., Chem. Abstr., 67: 54102m (1967); Glennon, R. A et al., J. Med. Chem., 31: 1968-1971 (1988); and Prasad, R. N et al., J. Med. Chem., 11: 1144-1150 (1968). These documents are discussed in WO 93/00313, publication date Jan. 7, 1993, which corresponds to U.S. application Ser. No. 07/894,771. See also WO 91/09594.
Despite the development of the above-mentioned compounds, the need continues to exist for new sigma receptor ligands and for methods for the treatment of central nervous system disorders and other conditions, utilizing such ligands.